Induction of the metabolism of etizolam by carbamazepine in humans.

OBJECTIVE: To examine the effect of carbamazepine on the single oral dose pharmacokinetics of etizolam. METHODS: Eleven healthy male volunteers received carbamazepine 200 mg/day or placebo for 6 days in a double-blind, randomized, crossover manner, and on the sixth day they received a single oral 1-mg dose of etizolam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test and Stanford Sleepiness Scale were conducted up to 24 h after etizolam dosing. Plasma concentration of etizolam was measured using high-performance liquid chromatography. RESULTS: Carbamazepine treatment significantly decreased the peak plasma concentration (17.5+/-4.1 ng/ml versus 13.9+/-4.1 ng/ml; P<0.05), total area under the plasma concentration-time curve (194.8+/-88.9 ng h/ml versus 105.9+/-33.0 ng h/ml; P<0.001), and elimination half-life (11.1+/-4.6 h versus 6.8+/-2.8 h; P<0.01) of etizolam. No significant change was induced by carbamazepine in the two pharmacodynamic parameters. CONCLUSIONS: The present study suggests that carbamazepine induces the metabolism of etizolam.

Inhibition of the metabolism of etizolam by itraconazole in humans: evidence for the involvement of CYP3A4 in etizolam metabolism.

OBJECTIVE: To clarify the involvement of cytochrome P450 (CYP) 3A4 in the metabolism of etizolam. METHODS: The effects of itraconazole, a potent and specific inhibitor of CYP3A4, on the single oral dose pharmacokinetics and pharmacodynamics of etizolam were examined. Twelve healthy male volunteers received itraconazole (200 mg/day) or placebo for 7 days in a double-blind randomized crossover manner, and on the 6th day they received a single oral 1-mg dose of etizolam. Blood samplings and evaluation of psychomotor function using the Digit Symbol Substitution Test and Stanford Sleepiness Scale were conducted up to 24 h after etizolam dosing. Plasma concentration of etizolam was measured by means of high-performance liquid chromatography. RESULTS: Itraconazole treatment significantly increased the total area under the plasma concentration-time curve (AUC; 213+/-106 ng rectangle h/ml versus 326+/-166 ng rectangle h/ml, P<0.001) and the elimination half-life (12.0+/-5.4 h versus 17.3+/-7.4 h, P<0.01) of etizolam. The 90% confidence interval of the itraconazole/placebo ratio of the total AUC was 1.38-1.68, indicating a significant effect of itraconazole. No significant change was induced by itraconazole in the two pharmacodynamic parameters. CONCLUSION: The present study suggests that itraconazole inhibits the metabolism of etizolam, providing evidence that CYP3A4 is at least partly involved in etizolam metabolism.

Development of a health guidance support system for lifestyle improvement. Committee of Health Evaluation Support System Council of Japan AMHTS Institutions.

OBJECTIVE: To provide automated advice for lifestyle adjustment based on an assessment of the results of a questionnaire and medical examination or health checkup data. METHODS: A system was developed that gathers data based on questions regarding weight gain, exercise, smoking, sleep, eating habits, salt intake, animal fat intake, snacks, alcohol, and oral hygiene; body mass index, resting blood pressure, fasting blood sugar, total cholesterol, triglycerides, uric acid and liver function tests. Based on the relationships between the lifestyle data and the health checkup data, a health assessment sheet was generated for persons being allocated to a multiple-risk-factor syndrome group. RESULTS: Health assessment and useful advice for lifestyle improvement were automatically extracted with the system, toward the high risk group for lifestyle related diseases. The system is operational. CONCLUSIONS: We developed a health guidance support system for lifestyle improvement. In comparison with conventional, limited advice methods, we developed a practical system that defined the necessity for lifestyle improvement more clearly, and made giving advice easier.

Carbamoyl phosphate synthetase I deficiency: molecular genetic findings and prenatal diagnosis.

We report a Japanese boy who died at Day 28 of life because of severe carbamoyl phosphate synthetase I (CPS1) deficiency that was proven by enzyme assay. By analysis of cDNA and genomic DNA, he was shown to be a compound heterozygote with two point mutations of the CPS1 gene, 840G>C leading to an aberrant splicing and 1123C>T (predicting Q375X). The 840G>C was a mutation described in another Japanese family. Since his parents carried each mutation heterozygously, we performed prenatal diagnosis at 16 weeks of his mother's next gestation by multiplex PCR and melting curve analysis in a single capillary containing two-color fluorescent (LC-Red 640 and LC-Red 705) probes on LightCycler. We analyzed genomic DNA extracted from amniotic cells and found that the fetus was homozygous for the wild-type alleles. At term a healthy girl was born without hyperammonemia.

[Observation of tinea unguium by neutral red staining].

To evaluate the viability of dermatophytes in tinea unguium, we applied neutral red staining (NRS) for nail powder obtained from direct microscopic examination (DME) of positive tinea unguium patients. The nail powder from tinea unguium patients by grinder was applied following three sets of examinations, NRS, DME, and culture on Mycosel medium. The positive rates of nail powder obtained from 50 tinea unguium patients were 35 (70%), 37 (74%) and 2 (4%), respectively. Correlation of three sets of examinations were as follows: twenty-five patients were NRS positive, DME positive and culture negative, 10 patients were NRS negative, DME positive and culture negative, and 8 patients were NRS positive, DME negative and culture negative. These findings suggest that application of NRS for nail powder from tinea unguium patients is a practical method for evaluation of the viability of fungal elements.

Dose-dependent augmentation effect of bromocriptine in a case with refractory depression.

1. A 52-year-old female with refractory depression had not responded to various treatments including electroconvulsive therapy and augmentation therapy with lithium or triiodothyronine. 2. Addition of bromocriptine 2.5-5 mg/day to imipramine improved her depressive symptoms. However, when the dose was increased to 15 mg/day to treat residual depressive symptoms, her clinical status deteriorated and returned to the original level. The dose reduction to 5mg/day again improved her depressive symptoms. 3. This report confirms the augmentation effect of bromocriptine for refractory depression. It also suggests that there is dose-dependency in this effect.

The first case of 4-hydroxybutyric aciduria in Japan.

We report a boy with 4-hydroxybutyric aciduria resulting from a deficiency of succinic semialdehyde dehydrogenase (SSADH). A boy, 1 year 5 months, showed delayed walk with hypotonia and could not speak meaningful words. The blood levels of lactate, pyruvate and amino acids were not elevated. Head magnetic resonance imaging (MRI) and electroenchephalography (EEG) were normal. Urinary organic acid analysis with gas chromatography-mass spectrometry (GCMS) revealed increased levels of 4-hydroxybutyric acid, glutaric acid, adipic acid and suberic acid. The concentrations of 4-hydroxybutyric acid and gamma-aminobutyric acid (GABA) were elevated in the serum and cerebrospinal fluid (CSF). SSADH activity in cultured lymphoblasts was 4.5% of the normal level. So far as we know this is the first Japanese patient diagnosed as 4-hydroxybutyric acid. Urinary organic acid analysis is necessary for the diagnosis of patients with unexplained psychomotor retardation.

The N-terminal prepeptide is required for the production of spore cortex-lytic enzyme from its inactive precursor during germination of Clostridium perfringens S40 spores.

A spore cortex-lytic enzyme of Clostridium perfringens S40 is synthesized during sporulation as a precursor consisting of four domains. After cleavage of an N-terminal preregion and a C-terminal proregion, inactive proenzyme (termed C35) is converted to active enzyme by processing of an N-terminal prosequence with germination-specific protease (GSP) during germination. The present results demonstrated that the cleaved N-terminal prepeptide remained associated with C35. After the isolated complex was denatured and dissociated in 6 M urea solution, removal of urea regenerated a prepeptide-C35 complex which produces active enzyme when incubated with GSP. However, isolated C35 alone could not be activated by GSP. The prepeptide-C35 complex was more heat stable than active enzyme. Thus, non-covalent attachment of the prepeptide to C35 is required to assist correct folding of C35 and to stabilize its conformation, suggesting that the prepeptide functions as an intramolecular chaperone. Recombinant proteins, which have prepeptide covalently bonded to C35, were processed by GSP as well as the in vivo prepeptide-C35 complex, and the full length of the N-terminal presequence was needed to fulfil its role. Although the C-terminal prosequence is present as an independent domain which is not involved in the activation process of the enzyme, it appears that the N-terminal prosequence contributes to the regulation of enzyme activity as an inhibitor of the enzyme.

Subjective symptoms acquisition system in a health promotion system for the elderly. Committee of System Development, Council of Japan AMHTS Institutions.

A previous report was concerned with the evaluation of quality of life using a Health Promotion System for the Elderly. In the present report, we describe one part of that system: a subjective symptoms acquisition and reporting system. The main purpose of this system is to permit any physician or nurse to uniformly employ questionnaires to acquire accurate subjective symptoms. This system is applied in three steps. First, the subjective answers to 21 questions displayed on a personal computer are obtained. These answers correspond to the basic subjective symptoms. Second, if a basic subjective symptom is "positive", more detailed questions are automatically generated. Finally, clear sentences regarding subjective symptoms are generated and output as a "finding report". This information is helpful to physicians and nurses in their health-counseling work. An artificial intelligence (AI) program based on "XpertRule" produces detailed questions which are generated by an interactive questionnaire using branching logical rules.

Pharmacogenetics of classical and new antipsychotic drugs.

Several classical antipsychotic drugs, i.e., chlorpromazine, haloperidol, perphenazine, thioridazine and zuclopenthixol; and some new neuroleptic drugs, i.e., risperidone and sertindole, are metabolized predominantly by cytochrome P450 (CYP) 2D6. Significant relationships have been reported between the steady state plasma concentrations (Css) of some classical neuroleptics and the CYP2D6 activity or genotype. Several of these drugs also potently inhibit the CYP2D6 activity. These facts explain several drug metabolic interactions of the classical drugs. Two studies failed to show that the CYP2D6 activity predicts the therapeutic effects of haloperidol or perphenazine. Some studies have suggested that the poor metabolizer phenotype is associated with the development of oversedation during treatment with the classical drugs, but other studies have been inconsistent or negative. The CYP2D6 phenotyping and genotyping appear to be useful in predicting the Css of some classical drugs, but their usefulness in predicting clinical effects must be further explored.

Simultaneous genotyping of alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) loci by amplified product length polymorphism (APLP) analysis.

Genotyping of the alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) loci is important in alcohol studies. We describe a method for simultaneous genotyping of ADH2 and ALDH2 based on amplified product length polymorphism (APLP) analysis. Two polymerase chain reaction (PCR) fragments for ADH2 (57 bp, 53 bp) and two for ALDH2 (78 bp, 73 bp) are simultaneously amplified. Nine banding patterns reflecting the genotypes of the ADH2 and ALDH2 loci are clearly and unambiguously distinguished. The APLP method seems to be particularly suited for large-scale population studies of ADH2 and ALDH2 loci because it is simple and rapid.

[Quality of life for patients with intractable diseases. Subjective satisfaction of patients with Parkinson's disease].

More than 20 years have passed since policies for dealing with intractable diseases have been instituted in Japan. This study was carried out to clarify which factors tend to promote a patient's subjective satisfaction with his or her quality of life. The subjects were 62 male and 51 female patients with Parkinson's disease. Their average age was 68.8 years. The results were as follows: 1. Patients placed more importance on trying to understand the pathophysiology of the disease than trying to improve their better-life with the disease. 2. Most male patients received care from a family member, whereas most female patients received care from a non-family member. 3. Multiple logistic regression analysis indicated that a) patients who understand how to improve their better-life with Parkinson's Disease are four times more satisfied(on-a subjective basis)than patients who do not understand how to improve their better-life, and b) patients who have a supportive caregiver are twice as satisfied as those who do not. These findings suggest that, in order to increase the subjective satisfaction of Parkinson's disease patients, it is important for them to have a supportive caregiver and to help them understand how to improve their better-life.

[Self-efficacy and related factors related in Parkinson's disease patients].

This study was designed to assess self-efficacy and the factors leading to higher self-efficacy in Parkinson's disease patients, as measured by General Self-Efficacy Scale (GSES). Questionnaires were mailed to patients with Parkinson's disease in Tokyo. This study surveyed 73 male and 70 female patients. Approximately 66.5% of the patients fell into the low self-efficacy group. Data was divided into 3 groups (high, moderate and low) and evaluated statistically. Approximately 66.5% of the patients fell into the low self-efficacy group. Patients in the high self-efficacy group exhibited the following features: Males: 1) The male patients in the high self-efficacy group tended to belong to more groups and had less trouble than any other groups in coping with their daily lives; 2) they generally had people to turn to for mental support outside their families, and for their daily life inside or outside their families; 3) they also felt confident that they had sufficient understanding of better life styles and how to exercise. Females: 1) The female patients in the high self-efficacy group tended to go out more often than any other groups and had places to go where they could practice hobbies and exercise; 2) they generally had people outside their families to turn to for mental support; 3) their subjective symptoms, such as freezing and dysarthria, tend to be less acute than in the moderate or low self-efficacy patients. 4) had les trouble than any other groups in coping with their housing accommodations; 5) they also felt confident that they understood how to exercise. In order to increase self-efficacy among Parkinson's disease patients, this study suggests that support, both social and psychological, and providing health education, are important.

Intracytoplasmic crystalline inclusions in dermal infiltrating cells of granulomatous contact dermatitis due to gold earrings.

A case of granulomatous contact dermatitis due to gold earrings for pierced ears was studied ultrastructurally. The patient was a 24-year-old woman, who had reddish brown papules on the earlobes. Patch test using gold sodium thiomalate proved strong positive, with blister formation. Histological observation of the papule showed dense cell infiltration throughout the full thickness of the dermis. Ultrastructurally, dermal infiltrating cells consisted of lymphocytes and histiocytes. Unusual crystalline inclusion bodies were observed in the cytoplasm of these cells. These structures were elliptical, not encapsulated and showed a regular fingerprint-like pattern of parallel lines along the short axis. The width of the lines and their intervals was 12 nm. These findings suggest that continuous contact between gold and dermis may induce inflammation, causing granulomatous changes and the development of crystalline inclusion bodies.

Dyskeratotic degeneration of epidermal cells in pityriasis rosea: light and electron microscopic studies.

We studied biopsies from twenty-nine patients with pityriasis rosea. All specimens showed features of subacute or chronic dermatitis as previously reported, but sixteen cases (55%) had dyskeratotic cells within the epidermis. Ultrastructurally, these cells contained an aggregation of tonofilaments, many vacuoles and intracytoplasmic desmosomes. Previously, only non-specific histological changes had been described in pityriasis rosea, but the presence of dyskeratotic cells seems to be a significant feature.

Analysis of transepidermal leukocyte chemotaxis in experimental dermatophytosis in guinea pigs.

In dermatophytosis, there is exocytosis of polymorphonuclear leukocytes (PMNs) toward the fungus-laden horny layer. To analyze this mechanism, we studied in vitro leukotactic properties of epidermal extracts prepared from lesions of experimental Trichophyton mentagrophytes infection in guinea pigs as well as fungus-derived chemotactic factors. Trichophyton mentagrophytes was found to release low-molecular-weight PMN chemotactic factors with its growth, like other microorganisms. Furthermore, it activated complement via the alternative pathway to produce complement-derived chemotactic factors in vitro. The epidermal extracts prepared from weakly inflammatory lesions of an early stage of T. mentagrophytes infection showed mild PMN chemotactic activity, which, as in those from irritated skin, was mostly due to the presence of low-molecular-weight chemotactic factors. After 8 days of infection, when prominent PMN migration took place together with the development of immune reactivity to fungus antigens, the epidermal extracts revealed strong leukotactic activity that showed a triphasic pattern by Sephadex G-75 chromatography similar to that observed in complement-activated serum. Since we could not demonstrate any deposition of immunoglobulins and complement on the fungal elements present in the horny layer, actual complement activation in vivo seems to occur after interaction of serum with soluble fungal components in the epidermis through both classic and alternative pathways. We think that the transepidermal migration of PMNs in dermatophytosis, together with contact sensitivity to fungal antigens, is responsible for induction of increased epidermopoiesis with resultant desquamation to eliminate the fungus-laden horny layer.